EP2321334A1

EP2321334A1 - New no releasing steroids derivatives

Info

Publication number: EP2321334A1
Application number: EP09781020A
Authority: EP
Inventors: Francesca Benedini; Laura Carzaniga; Ennio Ongini; Stefano Biondi
Original assignee: Nicox SA
Current assignee: Nicox SA
Priority date: 2008-08-05
Filing date: 2009-07-24
Publication date: 2011-05-18
Also published as: CA2731477A1; WO2010015529A1; US20110130376A1; CN102186874A

Abstract

The invention relates to compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof. The compounds are useful in the treatment of illnesses wherein the known steroid, parent or precursor steroid, is generally applied, with increased benefit in terms of pharmacological profile and fewer or milder side effects than those of the known steroids.

Description

"New NO releasing steroids derivatives"

The present invention relates to nitrooxy derivatives of known steroids, methods for their preparation, pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions for treating illnesses wherein the known steroid, parent or precursor steroid, is generally applied, with increased benefit in terms of pharmacological profile and fewer or milder side effects than those of the known steroids.

Therefore the compounds of the present invention may be used, according to the activity of the parent drug, as drugs having antiinflammatory activity at peripheral level, immunodepressive activity, angiostatic/angiogenetic activity, antiarthritic activity, in the therapy of neurodegenerative diseases on an inflammatory and traumatic basis of the nervous system, in the therapy of respiratory diseases such as asthma and COPD, in substitutive hormonal therapies, preferably in the post-menopause therapy, in rheumatic disease therapies, in renal disease therapies, in ocular disease therapies such as ocular hypertension, age- related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, in dermatological disease therapies, in autoimmune disease therapy in tumoral process therapies, in inflammatory pathologies affecting the gastrointestinal system. In the prior art nitrooxy derivatives of steroids, which are usable also as cardiovascular agents for the coronary insufficiency or angina pectoris therapy, are described. For example, German patent DE 2,222,491 describes the preparation of pregnane derivatives having in position 21 the -CH2-O-NO2 group. In said patent it is stated that said derivatives have a cardiotropic activity. This activity represents a drawback for said compounds, since they modify the cardiac frequency.

USP 3,494,941 describes steroid derivatives from 3- hydroxy-extrane or from extr-4 en-3 one, used as vasodilators in the treatment of cardiac affections such as coronary insufficiency and angina pectoris. In the structure of said compounds a ONO2 group is at the free end of the alkylene chain which is linked by an ether bond to the steroid in position 17. According to said patent it is possible to have nitrate groups also in the positions 3 and 16 of the steroidal structure. The same drawbacks mentioned above as regards the effects on the cardiac frequency can be repeated for the compounds of this patent.

USP 3,183,252 describes derivatives of 16-nitrate- alkylpregnanes wherein the alkyl group is linked to the pregnane structure by a carbon-carbon bond. The compounds according to said patent can be used as vasodilators. The same drawbacks reported for the above prior art can be repeated.

WO 98/15568 and WO 03/064443 in the name of the Applicant describe nitrate esters of steroidal compounds, wherein between the steroidal structure and the nitrooxy group a bivalent linking group is inserted. Said compounds show a good efficacy and/or good tolerability with respect to the corresponding precursors. Patent application WO 00/61604 in the name of the Applicant describes nitrooxy derivatives of steroidal compounds with various linking groups having at one end a nitrooxy group, and covalently linked with the other end to a steroidal compound. In said application the uses concern the compounds usable in the treatment of patients in oxidative stress. Said compounds contain in the molecule also a bivalent linking group which must be capable to prevent the free radicals production and is selected on the basis of the tests reported therein.

EP 1 336 602 describes new pharmacological compounds which can release nitric oxide and their use for the prevention and treatment of inflammatory, ischemic, degenerative and proliferative diseases. These compounds have a slower absorption compared to classic nitrate vasodilators. Between the compounds, steroidal nitroderivatives are disclosed.

WO 00/499993 describes nitrite, nitrate, thionitrite or thionitrate steroid derivatives optionally substituted in position 3, 11, 17 or 21 with a nitrate ester.

The Applicant has surprisingly and unexpectedly found a class of nitric oxide releasing compounds with a better bioavailability and/or a prolonged release of NO in comparison with the compounds known in prior art. In general the compounds of the present invention have a better drugability in comparison to the corresponding compounds of the prior art.

An object of the present invention is a compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

(D wherein :

Ri is -H or Ri is selected from

(A) -R^CH(NHR²) -C (0) -0-Y

(B) -R^CH (COOH) NH-C(O) -Y

(C) -R^CH(COOH)-O-C(O)-Y

(D) -C(O)CH(R³) -NH-C(O) -Y

(E) -C (O)CH₂-CH(R⁴) -NH-C (0) -Y

(F) -(Z)-Y (G)

(H)

:D wherein :

R¹ is selected from R^la)

-C(O)-S-CH₂-, -C(O)O-CH(CH₃)-, -C(O)O-CH₂-; preferably R^la is

R Ib' -C(O)-CH₂-, -C(O) - (CH₂) ₂-; preferably Rⁱⁱ³ is -C(O)-CH₂-; R² is -H or -C(O)CH₃;

R³ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl, preferably R³ is H or -CH₃; R⁴ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl, preferably R⁴ is H or -CH₃;

Z is -C(O) or -C(O)-X", wherein X" is 0, S or NR₁₁ wherein R₁₁ is H or a C₁-C₄ alkyl; preferably X" is 0;

R₂ is a straight or branched C₁-C_1O alkylene; preferably R₂ is a straight C₁-Ce alkylene; R₃ is H or a straight or branched C₁-C₄ alkyl, preferably R₃ is H or -CH_3/ more preferably R₃ is H; R₄ is -H, -CH₃; R_4A is -H, or R₄ and R_4A taken together are =CH₂; R₅ is -H, Cl;

R₆ is -H, Cl, F, CH₃; R_6a is -H, or R₆ and R₅ taken together are a double bond;

R_7a is H, or R₇ and R_7A taken together are a =0; R₈ is H, Cl, or R₇ and R₈ taken together are the group of formula (V)

Rsa is H, R₉ is -H, or R_8a and Rg taken together are a double bond Rio is -OH, RiOa is H, or Rio and Rio_a taken together are =0; Rn is -H, -Cl, -F;

Ri₂ is -H, CH₃; wherein R₄, R_4a, R₅, R₆, R_6a, R7, R7a, Rs, Rβa, R9, Rio, Rioa can be linked to the corresponding carbon atoms of the steroidal structure in position α or β; Y is selected from -Ri₃-CH(ONO₂)Ri₄ -Ri₃-CH (ONO₂) - (CRi₅Ri₆) _t~CH (ONO₂) R_i4

- [ (CH₂) o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q- (CRi₅Ri₆) t^~CH (ONO₂) R_i4

- [ (CH₂) _o-X] _p- [ (CH₂) _r-X] _s- (CH₂) _q-CH (ONO₂) - (CRi₅Ri₆) _t ^~CH (ONO₂) R₁₄ wherein

Ri₃ is a straight or branched C₁-C₁₀ alkylene; preferably Ri₃ is a straight Ci-C₆ alkylene; Ri4 is H or a straight or branched Ci-C₄ alkyl, preferably Ri₄ is H or -CH₃;

Ri₅ and Ri₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri₅ and Ri₆ are H or -CH_3; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2 ; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1 ; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1 ; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1;

X is O, S or NRi₇ wherein Ri₇ is H or a C₁-C₄ alkyl; preferably X is O; preferably Y is selected from -Ri₃-CH(ONO₂)Ri₄

-Ri₃-CH (ONO₂) - (CRi₅Ri₆) t"CH (ONO₂) R_i4

- [ (CH₂) o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q- (CRi₅Ri₆) t~CH (ONO₂) R₁₄ wherein

Ri₃ is a straight Ci-C₆ alkylene; Ri₄ is H or -CH₃;

Ri₅ and Ri₆ at each occurrence are independently H or -CH₃; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, X is 0; excluding the following structures from formula (I) :

Another embodiment of the present invention relates to compounds of formula (I) wherein Ri is selected from (A) -R^CH(NHR²) -C (0) -0-Y (B) -R^CH (COOH) NH-C (O) -Y (C) -R^CH (COOH) -0-C (0) -Y (D) -C (0) CH (R³) -NH-C (0) -Y (E) -C (0) CH₂-CH (R⁴) -NH-C (0) -Y (F) -(Z)-Y (G)

wherein :

R¹ is selected from R^la)

-C(O)-S-CH₂-, -C(O)O-CH(CH₃)-, -C(O)O-CH₂-; preferably R^la is

-C(O)-CH₂-, -C(O)-(CH₂)₂-; preferably R^lb is -C(O)-CH₂-; R² is -H or -C(O)CH₃; R³ is -H, -CH3, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl, preferably R³ is H; R⁴ is -H, -CH3, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl, preferably R⁴ is H;

R₂ is a straight or branched C₁-C₁O alkylene; preferably R₂ is a straight C₁-C₅ alkylene;

R₃ is H or a straight or branched C₁-C₄ alkyl, preferably R₃ is H or -CH_3;

R₄ is -CH₃, and it is linked to the 16 position of the steroidal structure in position β; R_4A is -H; R₅ is -H; R₆ is -H; R_6a is —H;

R₇ and R_7A taken together are a =0; R₈ is H;

Rs_a and Rg taken together are a double bond;

R_1O is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α;

R₁Oa is H; R₁₁ is -F;

R₁₂ is -H, CH₃; Y is selected from -R₁₃-CH(ONO₂)R₁₄

-R₁₃-CH (ONO₂) - (CR₁₅R₁₆) t^~CH (ONO₂) R₁₄ -[ (CH₂)_O-X_-P-. (CH₂) _r-X]_s- (CH₂) _q- (CR₁₅R₁₆) t-CH (ONO₂) R₁₄

- [ (CH₂) _o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q-CH (ONO₂) - (CR₁₅R₁₆) _t-CH (ONO₂) R₁₄ wherein Ri3 is a straight or branched Ci-Cio alkylene; preferably Ri3 is a straight Ci-C₆ alkylene;

Ri4 is H or a straight or branched Ci-C₄ alkyl, preferably Ri₄ is H or -CH₃; Ri₅ and Ri₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri₅ and Ri₆ are H or -CH_3; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2 ; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1 ; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1 ; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1 ;

X is O, S or NRi₇ wherein Ri₇ is H or a C₁-C₄ alkyl; preferably X is O; preferably Y is selected from -Ri₃-CH(ONO₂)Ri₄ -Ri₃-CH (ONO₂) - (CRi₅Ri₆) t"CH (ONO₂) R_i4

Ri₃ is a straight Ci-C₆ alkylene; Ri₄ is H or -CH₃; Ri₅ and Ri₆ at each occurrence are independently H or -CH₃; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, x is 0. Another embodiment of the present invention relates to compounds of formula (I) wherein Ri is selected from

(A) -R^CH(NHR²) -C (O) -O-Y

(B) -R^CH (COOH) NH-C (O) -Y

(C) -R^CH (COOH) -0-C(O)-Y

(D) -C (O)CH(R³) -NH-C (0) -Y

(E) -C(O)CH₂-CH(R⁴) -NH-C(O) -Y

(F) -(Z)-Y (G)

(H)

:D wherein :

R¹ is selected from R^la)

-C(O)-S-CH₂-, -C(O)O-CH(CH₃)-, -C(O)O-CH₂-; preferably R^la is -C(O)-CH₂-, -C(O)-(CH₂)₂-; preferably R^lb is -C(O)-CH₂-;

R² is -H or -C(O)CH₃; R³ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl, preferably R³ is H; R⁴ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl, preferably R⁴ is H;

R₃ is H or a straight or branched C₁-C₄ alkyl, preferably R₃ is H or -CH_3; R₄ is -CH₃, and it is linked to the corresponding carbon atoms of the steroidal structure in position β; R_4A is -H; R₅ is -H;

Re is -F and it is linked to the corresponding carbon atoms of the steroidal structure in position β; R_6a is -H;

R₇ and R_7A taken together are a =0; R₈ is H;

Rs_a and Rg taken together are a double bond; R₁O is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α; R₁Oa is H; Rn is -F; R₁₂ is -H, CH₃; Y is selected from

-R₁₃-CH(ONO₂)R₁₄ -Ri₃-CH (ONO₂) - (CRi₅Ri₆) t"CH (ONO₂) Ri₄

- [ (CH₂) o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q- (CRi₅Ri₆) t^~CH (ONO₂) R₁₄

- [ (CH₂) _o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q-CH (ONO₂) - (CRi₅Ri₆) _t~CH (ONO₂) R_i4 wherein Ri3 is a straight or branched Ci-Cio alkylene; preferably Ri3 is a straight Ci-C₆ alkylene;

Ri₄ is H or a straight or branched Ci-C₄ alkyl, preferably Ri₄ is H or -CH₃;

Ri₅ and Ri₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri₅ and Ri₆ are H or -CH₃; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2 ; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1 ; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1 ; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1; X is 0, S or NR_i7 wherein R_i7 is H or a C₁-C₄ alkyl; preferably X is 0; preferably Y is selected from -Ri₃-CH(ONO₂)Ri₄

-Ri₃-CH (ONO₂) - (CRi₅Ri₆) _t"CH (ONO₂) R_i4 -[ (CH₂)O-X_-P-. (CH₂) _r-X]_s- (CH₂) _q- (CRi₅Ri₆) t-CH (ONO₂) Ri₄ wherein

Ri₃ is a straight Ci-C₆ alkylene; Ri₄ is H or -CH₃;

Ri₅ and Ri₆ at each occurrence are independently H or -CH₃; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, X is 0.

Another embodiment of the present invention relates to compounds of formula (I) wherein Ri is selected from

(A) -R^CH(NHR²) -C (O) -O-Y

(B) -R^CH (COOH) NH-C (O) -Y

(C) -R^CH(COOH)-O-C(O)-Y

(D) -C(O)CH(R³) -NH-C(O) -Y

(E) -C (O)CH₂-CH(R⁴) -NH-C (0) -Y

(F) -(Z)-Y (G)

(H)

:D wherein :

R¹ is selected from R^la)

-C(O)-S-CH₂-, -C(O)O-CH(CH₃)-, -C(O)O-CH₂-; preferably R^la is

R^lb)

-C(O)-CH₂-, -C(O) - (CH₂) 2-; preferably R^lb is -C(O)-CH₂-; R² is -H or -C(O)CH₃;

R^J is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl, preferably R is H; R⁴ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl, preferably R⁴ is H;

R₃ is H or a straight or branched C₁-C₄ alkyl, preferably R₃ is H or -CH₃; R₄ is -H; R_4A is -H; R₅ is -H; R₆ is -H; R_6a is -H,

R₇ and R_7A taken together are a =0; R₈ is H; R_8a is H; R₉ is -H;

R₁O is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α; R₁Oa is H; Rn is H;

Ri₂ is -H, CH₃; Y is selected from -Ri₃-CH(ONO₂)Ri₄ -Ri₃-CH (ONO₂) - (CRi₅Ri₆) t"CH (ONO₂) R_i4

- [ (CH₂) _o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q-CH (ONO₂) - (CRi₅Ri₆) _t~CH (ONO₂) R₁₄ wherein

Ri₃ is a straight or branched Ci-Cio alkylene; preferably Ri₃ is a straight Ci-C₆ alkylene;

Ri₅ and Ri₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri₅ and Ri₆ are H or -CH₃; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1;

X is 0, S or NRi₇ wherein R₁₇ is H or a C₁-C₄ alkyl; preferably X is 0; preferably Y is selected from

-Ri₃-CH(ONO₂)Ri₄

-Ri₃-CH (ONO₂) - (CRi₅Ri₆) _t"CH (ONO₂) R_i4

- [ (CH₂) o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q- (CRi₅Ri₆) t^~CH (ONO₂) R₁₄ wherein

Ri₃ is a straight Ci-C₆ alkylene; Ri₄ is H or -CH₃; Ri5 and Ri6 at each occurrence are independently H or -CH₃; o and r are integers from 1 to 4, p and s are from 1 to 4 ; q is from 0 to 4, t is 0 or 1,

X is 0.

(A) -R^CH(NHR²) -C (O) -O-Y

(B) -R^CH(COOH)NH-C(O)-Y

(C) -R^CH(COOH)-O-C(O)-Y

(D) -C(O)CH(R³) -NH-C(O) -Y

(E) -C (O)CH₂-CH(R⁴) -NH-C (0) -Y

(F) -(Z)-Y (G)

(H)

:D

OMe wherein :

R¹ is selected from

R )l¹a_\

-C(O)-S-CH₂-, -C(O)O-CH(CH₃)-, -C(O)O-CH₂-; preferably R^la is

-C(O)-CH₂-, -C(O) - (CH₂) ₂-; preferably Rⁱⁱ³ is -C(O)-CH₂-; R² is -H or -C(O)CH₃;

R³ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl, preferably R³ is H;

R⁴ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl, preferably R⁴ is H; Z is -C(O) or -C(O)-X", wherein X" is 0, S or NR₁₁ wherein R₁₁ is H or a C₁-C₄ alkyl; preferably X" is 0;

R₂ is a straight or branched C₁-C_1O alkylene; preferably R₂ is a straight C₁-C₅ alkylene;

R₃ is H or a straight or branched C₁-C₄ alkyl, preferably R₃ is H or -CH₃;

R₄ is -H;

R_4A is -H;

R₅ is -H;

R₆ is -H; R_6a is -H,

R₇ and R_7A taken together are a =0;

R₈ is H;

R_8a is H;

R₉ is -H; Rio is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α;

Rioa is H;

Rn is H; Ri₂ is -H, CH₃;

Y is selected from

-Ri₃-CH(ONO₂)Ri₄

-Ri₃-CH (ONO₂) - (CRi₅Ri₆) t^~CH (ONO₂) R_i4

- [ (CH₂) o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q- (CRi₅Ri₆) t^~CH (ONO₂) R₁₄ - [ (CH₂) _o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q-CH (ONO₂) - (CRi₅Ri₆) _t~CH (ONO₂) R₁₄ wherein

Ri₅ and R₁₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri₅ and Ri₆ are H or -CH₃; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1;

X is 0, S or NRi₇ wherein Ri₇ is H or a C₁-C₄ alkyl; preferably X is 0; preferably Y is selected from -Ri₃-CH(ONO₂)Ri₄

-Ri₃-CH (ONO₂) - (CRi₅Ri₆) _t~CH (ONO₂) R_i4

Ri3 is a straight Ci-C₆ alkylene; Ri₄ is H or -CH₃;

Ri5 and Ri6 at each occurrence are independently H or -CH₃; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, X is 0.

Another embodiment of the present invention relates to compounds of formula (I) wherein Ri is -H;

R2 is a straight or branched C1-C10 alkylene; preferably R2 is a straight Ci-C₅ alkylene;

R3 is H or a straight or branched Ci-C₄ alkyl, preferably R₃ is H or -CH₃;

R₄ is -CH3, and it is linked to the 16 position of the steroidal structure in position β;

R_4A is -H;

R₅ is -H;

R₆ is -H;

R_6a is -H; R₇ and R_7A taken together are a =0;

R₈ is H;

Rs_a and Rg taken together are a double bond;

Rio is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α; Rioa is H;

Rn is -F;

R12 is -H, CH₃. Another embodiment of the present invention relates to compounds of formula (I) wherein

Ri is -H;

R₄ is -CH3, and it is linked to the corresponding carbon atoms of the steroidal structure in position β; R_4A is -H; R₅ is -H;

Re is -F and it is linked to the corresponding carbon atoms of the steroidal structure in position β;

R_6a is -H; R₇ and R_7A taken together are a =0; R₈ is H;

Rs_a and Rg taken together are a double bond;

Rio is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α; Rioa is H; Rn is -F; R12 is -H, CH₃.

Another embodiment of the present invention relates to compounds of formula (I) wherein

Ri is -H;

R₃ is H or a straight or branched Ci-C₄ alkyl, preferably R₃ is H or -CH₃; R₄ is -H; R_4A is -H;

R₅ is -H; R₆ is -H; R_6a is -H,

R₇ and R_7A taken together are a =0; R₈ is H; R_8a is H; R₉ is -H;

Rio is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α;

Rioa is H; Rn is H;

Ri₂ is -H, CH₃.

R3 is H or a straight or branched Ci-C₄ alkyl, preferably R₃ is H or -CH₃; R₄ is -H;

R_4A is -H;

R₅ is -H;

R₆ is -H;

R_6a is -H, R₇ and R_7A taken together are a =0;

R₈ is H;

R_8a is H;

R₉ is -H;

Rioa is H;

Rn is H;

R12 is -H, CH₃. Another embodiment of the invention provides a compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

(D wherein Ri is

(F) -(Z)-Y wherein:

R2 is a straight or branched C₁-C₁O alkylene; preferably R2 is a straight C₁-Ce alkylene; R3 is H or a straight or branched C₁-C₄ alkyl, preferably R3 is H or -CH₃, more preferably R2 is H; R₄ is -H, -CH₃; R_4A is -H, or R₄ and R_4A taken together are =CH₂; R₅ is -H, Cl;

R₆ is -H, Cl, F, CH₃; R_6a is -H, or R₆ and R₅ taken together are a double bond; R_7a is H,

R₇ and R_7A taken together are a =0; R₈ is H, Cl, or R₇ and R₈ taken together are the group of formula (V)

(V)

Rsa is H, R₉ is -H, or R_8a and Rg taken together are a double bond Rio is -OH,

Rioa is H, or Rio and Rio_a taken together are =0; Rn is -H, -Cl, -F; Ri₂ is -H, CH₃; wherein R₄, R_4a, R₅, R₆, R_6a, R7, R7a, Rs, Rβa, R9, Rio, Rioa can be linked to the corresponding carbon atoms of the steroidal structure in position α or β; Y is selected from -Ri₃-CH(ONO₂)Ri₄ -Ri₃-CH (ONO₂) - (CRi₅Ri₆) t^~CH (ONO₂) R_i4

Ri₃ is a straight or branched C₁-C₁0 alkylene; preferably Ri₃ is a straight Ci-C₆ alkylene;

Ri₄ is H or a straight or branched Ci-C₄ alkyl, preferably Ri₄ is H or -CH₃; Ri₅ and Ri₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri₅ and Ri₆ are H or -CH_3; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2 ; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1 ; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1 ; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1;

-Ri₃-CH (ONO₂) - (CRi₅Ri₆) t"CH (ONO₂) R_i4

Ri₃ is a straight Ci-C₆ alkylene; Ri₄ is H or -CH₃;

(H₁:

(H₁₁: R-,

(H₁₁₁;

(H₁,

Another embodiment of the invention provides a compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof IR^LX3

(i:

(H)

:D

wherein :

R2 is a straight or branched C1-C10 alkylene; preferably R2s a straight Ci-Cε alkylene; R₃ is H or a straight or branched Ci-C₄ alkyl, preferably R₃ is H or -CH₃, more preferably R₃ is H;

R₄ is -H, -CH₃;

R_4A is -H, or R₄ and R_4A taken together are =CH₂;

R₅ is -H, Cl;

R₆ is -H, Cl, F, CH₃;

R_6a is -H, or R₆ and R₅ taken together are a double bond; R_7a is H,

R₇ and R_7A taken together are a =0;

R₈ is H, Cl, or R₇ and R₈ taken together are the group of formula (V)

(V)

R_8a is H,

R₉ is -H, or R_8a and Rg taken together are a double bond

Rio is -OH, Ri_Oa is H, or Rio and Rio_a taken together are =0;

Rn is -H, -Cl, -F;

R12 is -H, CH₃; wherein R₄, R_4a, R₅, R₆, R_6a, R₇, R_7a, R₈, R_8a, R₉, Ri₀, Rio_a can be linked to the corresponding carbon atoms of the steroidal structure in position α or β; Y is selected from -Ri₃-CH(ONO₂)Ri₄ -Ri₃-CH (ONO₂) - (CRi₅Ri₆) t"CH (ONO₂) Ri₄

Ri4 is H or a straight or branched Ci-C₄ alkyl, preferably Ri₄ is H or -CH_3;

Ri₅ and R_i6 are ^at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri₅ and Ri₆ are H or -CH_3; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2 ; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1 ; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1 ; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1; X is 0, S or NR_i7 wherein R_i7 is H or a C₁-C₄ alkyl; preferably X is 0;

preferably Y is selected from -Ri₃-CH(ONO₂)Ri₄ -Ri₃-CH (ONO₂) - (CRi₅Ri₆) _t~CH (ONO₂) R_i4

- [ (CH₂) o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q- (CRi₅Ri₆) t~CH (ONO₂) R_i4 wherein

Ri₃ is a straight Ci-C₆ alkylene; Ri₄ is H or -CH₃; Ri₅ and Ri₆ at each occurrence are independently H or -CH₃; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, X is O; excluding the following structures from formula (I^'

Another embodiment of the invention provides a compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

(D wherein Ri is (A) -R^CH (NHR²) -C (0) -0-Y (B) -R^CH (COOH) NH-C (0) -Y

(C) -R^CH (COOH) -0-C(O)-Y

(D) -C (O)CH(R³) -NH-C (0) -Y

(E) -C(O)CH₂-CH(R⁴) -NH-C(O) -Y wherein :

R¹ is selected from: R^la)

-C(O)-S-CH₂-, -C(O)O-CH(CH₃)-, -C(O)O-CH₂-; preferably R^la is

R³ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl; preferably R³ is H or -CH₃; R⁴ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) 2-, benzyl; preferably R⁴ is H or -CH₃;

R₂ is a straight or branched Ci-Cio alkylene; preferably R₂ is a straight Ci-C₆ alkylene;

R₃ is H or a straight or branched Ci-C₄ alkyl, preferably R₃ is H or -CH_3/ more preferably R₆ is H; R₄ is -H, -CH₃;

R_4A is -H, or R₄ and R_4A taken together are =CH₂;

R₅ is -H, Cl;

R_7a is H,

R₇ and R_7A taken together are a =0;

R₈ is H, Cl, or R₇ and R₈ taken together are the group of formula (V)

(V)

Ri₂ is -H, CH₃; wherein R₄, R_4a, R₅, R₆, R_6a, R7, R7a, Rs, Rβa, R9, Rio, Rioa can be linked to the corresponding carbon atoms of the steroidal structure in position α or β; Y is selected from -Ri₃-CH(ONO₂)Ri₄ -Ri₃-CH (ONO₂) - (CRi₅Ri₆) t^~CH (ONO₂) R_i4

Ri₅ and R₁₆ are ^at each occurrence independently H or a straight or branched C₁-C₁0 alkylene, preferably Ri₅ and Ri₆ are H or -CH₃; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1;

X is 0, S or NR₁₇ wherein Ri₇ is H or a C₁-C₄ alkyl; preferably X is 0; preferably Y is selected from -Ri₃-CH(ONO₂)Ri₄

-Ri₃-CH (ONO₂) - (CRi₅Ri₆) _t~CH (ONO₂) R_i4

Ri3 is a straight Ci-Cε alkylene;

Ri₄ is H or -CH₃;

Ri5 and Ri6 at each occurrence are independently H or -CH₃; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1,

X is O; excluding the following structures from formula (I) :

Another embodiment of the invention provides a compound selected from the group:

⁽i: (2:

o:

:i2)

:i3)

:i4)

:4i)

:42)

:43)

In another aspect of the invention, there is provided a compound of formula (I) for the use in the treatment of rheumatic diseases, renal and bronchial pathologies, ocular and dermatological diseases, autoimmune diseases, tumoral processes, also in combination with chemotherapeutic and/or radiotherapeutic treatments, in neurodegenerative diseases, for example in spinal lesions from trauma and in the post- transplant therapy. Furthermore inflammatory pathologies affecting the gatrointestinal system (Crohn disease, ulcerous colitis and IBD (inflammatory bowel diseases) can be mentioned.

In yet another aspect of the invention, there is provided a pharmaceutical composition comprising an acceptable carrier and a pharmaceutically effective amount of a compound of formula (I) and/or a salt or stereoisomer thereof, or such a pharmaceutical composition in a suitable form for parenteral, oral and topic use, such as for example sublingual, inhalatory, suppository, transdermal, enema, according to the well known techniques in the art, together with the usual excipients; see for example the publication "Remington's Pharmaceutical Sciences" 15th Ed.

The amount on a molar basis of the active principle in said compositions is generally the same or lower than that of the corresponding precursor drug.

The daily administrable doses are those of the precursor drugs, or optionally lower. The precursor daily doses can be found in the publications of the field, such for example in the "Physician's Desk reference".

As used herein, the terms "treat," "treating" or "treatment" includes preventative (e.g., prophylactic) and palliative treatment.

As used herein, the term "pharmaceutically acceptable" means the carrier, diluent, excipients and/or salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As used herein, the term "alkyl" means a straight or branched chain saturated hydrocarbon. Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2- methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl, octyl and the like.

The term "Ci-Cio alkylene" as used herein refers to branched or straight alkylene groups including methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, t-butylene, pentylene, hexylene, octylene and the like.

Synthesis procedure In general the term "amino protecting group" as used herein refers to Boc, Fmoc or those described in T. W. Greene "Protective groups in organic synthesis", Wiley- Interscience, 2007, 4th edition. The term " carboxylic protecting group" as used herein refers to tert-butyl ester and those described in T. W. Greene "Protective groups in organic synthesis", Wiley- Interscience, 2007, 4th edition.

The term "diol protecting group" as used herein refers to acetal, such as p-methoxybenzylidene, butylidene, and those described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4nd edition; The term "hydroxyl protecting group" as used herein refers to silyl ethers, such as trimethylsilyl, tert-butyl- dimethylsilyl or trityl and those described in T. W. Greene "Protective groups in organic synthesis", Wiley- Interscience, 2007, 4th edition. 1) The compound of general formula (I) as above defined wherein R₁ is H, R₂, R₃, R₄, FUa, Rs, Re, Re_a, R7, R7a, Rs, Rs_a, R₉, Rio, Rioa are as above defined, can be obtained: 1.1) by reacting a compound of formula (Ha), i.e. the precursor corticosteroid,

O—H

(Ha) wherein R₄, R_4a, R₅, R₆, R_6a, R₇, R_7a, R₈, R_8a, R₉, R_i0, Rio_a are as above defined with a compound of formula (HIa)

(RAO)₃C-R₂-CH(Q)R₃

(HIa) wherein : R_A is straight alkyl C1-C10, R2 and R₃ are as above defined and Q is ONO₂ or Qi, wherein Qi is selected from the group consisting of: a chlorine atom, a bromine atom, a iodine atom, a mesyl group or a tosyl group; the reaction is carried out in presence of an organic acid such as p- toluensulfonic acid. The reaction is carried out in an inert organic solvent such as tetrahydrofuran, dioxane, at a temperature from -20⁰C and 40⁰C. The reaction is completed within a time range from 30 minutes to 36 hours and 1.2) hydrolyze the ortho ester of formula (lib) obtained in 1.1)

(lib) wherein R4, R4_a, R5/ Rβ/ Rβa/ R7/ R7a/ Rs / Rsa^ R9/ Rio/ Rioa/ RA and Q are as above defined, by reacting the compound (lib) with an organic acid such as AICI3, acetic acid, ossalic acid in an organic aqueous solvent such as methanol, ethanol, propanol, isopropanol at a temperature from -20⁰C and 40⁰C. The reaction is completed within a time range from 30 minutes to 36 hours and 1.3) when Q is Qi, by reacting the compound obtained in the step 1.2) with a nitrate source such as silver nitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate (wherein alkyl is Ci- Cio alkyl) in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF; the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent. Alternatively, the reaction with AgNO₃ can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between about 100-180⁰C for time range about 1-60 min. Preferred nitrate source is silver nitrate.

The compounds of formula (Ha) are commercially available

2) The compound of general formula (I) as above defined wherein R₂, R₃, R₄, FUa, Rs, Re, Re_a, R7, R7a, Rs, Rs_a, Rg, Rio, Rioa are as above defined, and Ri is selected from:

(A) -R^CH(NHR²) -C (O) -O-Y

(B) -R^CH(COOH)NH-C(O)-Y

(C) -R^CH(COOH)-O-C(O)-Y (F) -(Z)-Y

(G)

(H)

(I!

wherein

R¹ is selected from the group R^la) as above defined, R² is as above defined, Z is -C(O)O- and

Y is as above defined, can be synthesized:

2.1) by reacting a compound of formula (1Ic]

wherein R₂, R₃, R₄, R4a, R₅, R₆, R_6a, R₇, R_7a, R₈, R₉, R₁₀, R_10a are as above defined and W is -H or -COC1 with a compound of the following formulae (A₁; W₁-R^la'-CH(NHR^2a) -C(O) -0-Y'

(B₁) W₁-R ,¹1^a'-CH(COOP)NH-C(O)-Y' (C₁) W₁-R¹^-CH(COOP)-O-C(O)-Y' (F₁) W₁-O-Y' (G₁)

OMe wherein

Wi is -H or R_BOC(O)- wherein R_B is pentafluorophenyl, 4- nitrophenyl, R^la' ) is selected from

'CH₉ —o

-S-CH₂-, -0-CH(CH₃)-, -0-CH₂-;

R^2a is -H or -C(O)CH₃ or P₂ wherein P₂ is a amino protecting group, P is a carboxylic protecting group, Pi is a diol protective group,

Y' is

-Ri₃-CH(Q)Ri₄

-Ri₃-CH (Q) - (CRi₅Ri₆) t~CH (Q) R₁₄ -[ (CH₂)O-X_-P-. (CH₂) _r-X]_s- (CH₂) _q- (CRi₅Ri₆) t-CH (Q) Ri₄

-[ (CH₂) ₀-X]p-[ (CH₂) _r-X] _s- (CH₂) _q-CH (ONO₂)- (CRi₅Ri₆Jt-CH(Q)Ri₄ wherein

X, Ri₃, Ri₄, Ri₅, Ri₆, o, p, q, r, s and t are as above defined, Q is ONO₂ or Qi, wherein Qi is selected from Cl, Br, I, a mesyl group or a tosyl group;

2.1. a) The reaction of a compound of formula (lie) wherein

W is H with a compound of formula (Ai) , (Bi) , (Ci) , (Fi) ,

(Gi), (Hi) or (Ii) wherein Wi is R_BOC (0) - is carried out in presence of a catalyst, such as DMAP or in the presence of DMAP and a Lewis acid such as Sc(OTf)₃ or Bi(OTf)₃ in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20°C and 40⁰C. The reaction is completed within a time range from 30 minutes to 36 hours.

2.1.b) The reaction of a compound of formula (lie) wherein W is COCl with a compound of formula with a compound of formula (A₁), (B₁), (C₁), (F₁), (G₁), (H₁) or (I₁) wherein W₁ is H may be carried out in presence of an organic base such as N, N-dimethylamino pyridine (DMAP), triethylamine, pyridine. The reaction is carried out in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20⁰C and 40⁰C. The reaction is completed within a time range from 30 minutes to 36 hours.

2.2) when Q is Q₁, by converting the compound obtained in the step 2.1) into nitro derivative by reaction with a nitrate source according to the method described in 1.3) and

2.3) optionally deprotecting the compounds obtained in step 2.1) or 2.2) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4^nd edition. Trifluoroacetic acid or anhydrous inorganic acid are the preferred method for removing Boc protecting group, organic base such as piperidine is the preferred method for removing Fmoc protecting group. Aqueous or anhydrous organic or inorganic acid is the preferred method for removing t-butyl ester protecting group. Hydrochloric acid in tetrahydrofurane is the preferred method for removing acetal protecting group. Alternatively the compound of general formula (I) as defined in 2) wherein R₁ is selected from (A), (B), (C), (F), (G), (H), (I), can be synthesized 3.1) by reacting a compound of formula (lie) wherein R2,

R₃, R₄, R_4a, R₅, R₆, R_6a, R₇, R_7a, R₈, R_8a, R₉, R₁₀, R_10a and W are as above defined with a compound of formula (A₂) Wi-R^la'-CH(NHR^2a) -C (O) -O-P (B₂) W₁-R^13' -CH (COOP) -NH-R^2a

(C₂;

wherein

Wi is -H or R_BOC(O)- wherein R_B is pentafluorophenyl, 4- nitrophenyl,

R^la', R^2a, R³, R⁴, P, P₁ are as above defined and P₃ is a alpha hydroxyl acid protecting group such as 4-oxo-l,3- dioxolane; 3.1. a) The reaction of a compound of formula (lie) wherein W is H with a compound of formula (A₂) , (B₂) , (C₂) , (G₂) ,

(H₂), (I₂) wherein Wi is R_BOC (O) - is carried out according to the method described in 2.1. a) .

3.1.b) The reaction of a compound of formula (lie) wherein The reaction of a compound of formula (lie) wherein W is COCl with a compound of formula (A₂) , (B₂) , (C₂) , (G₂) ,

(H₂), (I₂) wherein Wi is H is carried out according to the method described in 2.1.b), and

3.2) deprotecting the compounds obtained in step 3.1) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4^nd edition, hydrochloric acid or anhydrous inorganic acid are the preferred method for removing alpha hydroxy acid protecting group, and

3.3) by reacting a compound of formula (Hd) obtained in the step 3.2)

) R₃

(Hd) wherein R₂, R3, R4, R₄₃, Rs^ Rβ/ Rβa/ R7/ R7a/ Rs / Rsa^ R9/ Rio and Rioa are as above defined and R_4c is a radical selected from the following meaning

(A₃) -R^la-CH(NHR^2a) -C (O) -OH (B₃) -R ,1a-CH(COOP) -NH₂ (C₃) -R ,1a-CH (COOH) -OH (G₃)

wherein R¹ is selected from the group R^la) as above defined, R^2a is as above defined, with a compound of formula

(Via) W₂-Ri₃-CH(Q)R₁₄

(VIb) W₂-R₁₃-CH (Q) - (CR₁₅R₁₆) t^~CH (Q) R₁₄ (VIc) W₂- [ (CH₂)₀-X]p- [ (CH₂) r-X] s- (CH₂) _q- (CR₁₅R₁₆) _t ^~CH (Q) R₁₄

(VId) W₂- [ (CH₂) _o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q-CH (Q) - (CR₁₅R₁₆) _t-CH (Q) R₁₄ wherein W₂ is selected from HO-, Cl, Br, I, -COOH, -COCl,

-C(O)ORB wherein R_B is as above defined;

W₂ is -OH, Cl, Br, I when R_4c is selected from (A₃) , (G₃) , (H₃), (I₃) or W₂ is -COOH, -C(O)OR_B, -CO-Cl when R_4c is selected from (B₃) , (C₃) ;

3.3. a) the reaction of the compound of formula (Hd) wherein R_4c is selected from (A₃), (G₃), (H₃), (I₃), with a compound of formula (Via) , (VIb) , (VIc) or (VId) wherein W₂ is Cl, Br, I is carried out in the presence of a organic base such as 1, 8-diazabiciclo [5.4.0 ] undec-7-ene (DBU), N, N- diisopropylethyl amine, diisopropylamine or an inorganic base such as alkaline-earth metal carbonate or hydroxide, potassium carbonate, cesium carbonate, in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone, acetonitrile, a polyhalogenated aliphatic hydrocarbon at a temperature from -20⁰C and 40⁰C, preferably from 5°C to 25°C. The reaction is completed within a time range from 1 to 8 hours. When W₃ is chosen among chlorine or bromine the reaction is carried out in presence iodine salts such as KI . 3.3.b) the reaction of a compound of formula (lid) wherein R_4c is a radical selected (A₃), (G₃), (H₃), (I₃), with a compound of formula (Via) , (VIb) , (VIc) or (VId) wherein W₂ is -OH is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC), N' - (3-dimethyl aminopropyl) -N-ethylcarbodiimide hydrochloride (EDAC), N, N' -carbonyldiimidazole (CDI), optionally in the presence of a base, for example DMAP, in an inert organic solvent dry such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20⁰C and 50⁰C. The reaction is completed within a time range from 30 minutes to 36 hours;

3.3.c) the reaction of a compound of formula (lid) wherein

R_4c is (B₃) or (C₃) with a compound of formula (Via) , (VIb) ,

(VIc) or (VId) wherein W₂ is -COOH is carried out according to the method described in 3.3.b) or in presence of other condensing reagents such as O- (7-azabenzotriazol-l-yl) - N, N, N ' , N ' -tetramethyluronium hexafluorophosphate (HATU); 3.3. d) The reaction of a compound of formula (Hd) wherein R_4c is (B₃) or (C3) with a compound of formula (Via) , (VIb) , (VIc) or (VId) wherein W₂ is -COCl may be carried out according to the method described in 2.1.b); 3.3.e) the reaction of a compound of formula (Hd) wherein R_4c is (B₃) or (C₃) with a compound of formula (Via) , (VIb) , (VIc) or (VId) wherein W₂ is R_BOC (0) - is carried out according to the method described in 2.1. a), and 3.4) when Q is Qi, by converting the compound obtained in the step 3.3) into nitro derivative according to the method described in 1.3) and 3.5) deprotecting the compounds obtained in step 3.3) or 3.4) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4^nd edition. 4) The compound of general formula (I) as above defined wherein R₂, R₃, R₄, R_4a, R₅, R₆, R_6a, R₇, R_7a, R₈, R_8a, R₉, R₁₀, Rio_a are as above defined and rl is selected from: (A) -R^CH(NHR²) -C (O) -O-Y

(B) -R^CH(COOH)NH-C(O)-Y

(C) -R^CH (COOH) -0-C(O)-Y

(D) -C (O)CH(R³) -NH-C (0) -Y

(E) -C (O)CH₂-CH(R⁴) -NH-C (0) -Y (F) -(Z)-Y wherein

R¹ is selected from the group R^lb) as above defined, R², R³ R⁴ and Y are as above defined, Z is -C(O)-, can be synthesized:

4.1) by reacting a compound of formula (Hc) as above defined wherein R₂, R₃, R₄, R_4a, R₅, R₆, R_6a, R₇, R_7a, R₈, Rs_a, R₉, Rio, RiOa are as above defined and W is H, with a compound of formula:

(A₄) W₃-R¹-CH(NHR^2a) -C (O) -O-Y'

(B₄) Ws-R^CH (COOP)NH-C (O) -Y' (C₄) W₃-R¹-CH(COOP) -0-C (0) -Y'

(Di) W₃-C(O)CH(R³) -NH-C(O) -Y'

(Ei) W₃-C (0) CH₂-CH (R⁴) -NH-C (0) -Y'

(F₂) W₃-(Z)-Y' wherein W₃ is HO- or R_B0- wherein R_B is as above defined, R¹, R^2a, R³, R⁴, P and Y' are as above defined;

4.1. a) The reaction of a compound of formula (lie) wherein

W is H with a compound of formula (A₄) , (B₄) , (C₄) , (Di) ,

(Ei) or (F₂) wherein W₃ is R_B0- is carried out as reported in 2.1. a) ; 4.1.b) the reaction of a compound of formula (lie) wherein

W is H with a compound of formula (A₄) , (B₄) , (C₄) , (Di) ,

(Ei) or (F₂) wherein W₃ is HO-, is carried out as reported in 3.3.b) ; and 4.2) when Q is Qi, by reacting the compound obtained in the step 4.1) with a nitrate source according to the method described in 1.3) and

4.3) optionally deprotecting the compounds obtained in step 4.1) or 4.2) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4^nd edition .

Alternatively the compound of general formula (I) as defined in 4), wherein Ri is selected from (A), (B), (C), (F), (G), (H), (I), can be synthesized

4.4) by reacting a compound of formula (lie) as above defined with a compound of formula

(A₅) W₃-R^CH(NHR²³) -C (0) -Q-P (B₅) Ws-R^CH (COOH) -NH-R^2a (C₅)

(D₂) W₃-C (0) -CH(R³) -NH-R^2a (E₂) W₃-C (0) -CH₂-CH(R⁴) -NH-R^2a wherein :

W₃, R¹, R^2a, R³, R⁴, P and P₃ are as above defined;

4.4. a) the reaction of a compound of formula (lie) with a compound of formula (A₅) , (B₅) , (C₅) , (D₂) or (E₂) wherein W₃ is HO-, is carried out according to the method described in

4.1.b) ,

4.4.b) the reaction of a compound of formula (lie) wherein

W is H with a compound of formula (A₅) , (B₅) , (C₅) , (D₂) or

(E₂) wherein W₃ is R_B0- is carried out according to the method described in 4.1. a), and

4.5) deprotecting the compounds obtained in step 4.4. a) or 4.4.b) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4^nd edition, and

4.6) by reacting a compound of formula (He) obtained in the step 4.5)

(He) wherein R₂, R3, R4, R4a/ R5/ Rβ/ Rβa/ R7/ R7a/ Rs / Rsa/ R9/ Rio/ Rio_a are as above defined and R_4f is a radical selected from: (A₆) -R^CH(NHR²³) -C (O)OH (B₆) -R^CH(COOP)-NH₂ (C₆) -R^CH(COOH)-OH (D₃) -C (O) -CH(R³) -NH₂ (E₃) -C(O) -CH₂-CH(R⁴) -NH₂ wherein R¹ is selected from the group R^lb) as above defined,

R^' 2a R , R⁴ and P are as above defined, with a compound of formula

(Via) W₂-R₁₃-CH(Q)R₁₄

(VIb) W₂-R₁₃-CH (Q) - (CR₁₅R₁₆) _t~CH (Q) R₁₄

(VIc) W₂- [ (CH₂)O-X_-P-. (CH₂) _r-X]_s- (CH₂) _q- (CR₁₅R₁₆) t-CH (Q) R₁₄

(VId) W₂- [ (CH₂) _o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q-CH (Q) - (CR₁₅R₁₆) _t-CH (Q) R₁₄ wherein

W₂ is HO-, Cl, Br, I when R_4f is (A₆), or W₂ is -COOH, - C(O)OR_B or -COCl when R_4f is (B₆), (C₆), (D₃) or (E₃); 4.6. a) the reaction of the compound of formula (He) wherein R_4f is (A₆) , with a compound of formula (Via) ,

(VIb), (VIc), (VId) wherein W₂ is Cl, Br, I, is carried out according to the method described in 3.3.a); 4.6.b) the reaction of the compound of formula (He) wherein R_4f is (B₆) , (C₆) , (D₃) or (E₃) with a compound of formula (Via) , (VIb) , (VIc) , (VId) wherein W₂ is OH, is carried out according to the method described in 2.1.c) . 4.6.c) the reaction of the compound of formula (He) wherein R_4f is (B₆) , (C₆) , (D₃) or (E₃) with a compound of formula (Via) , (VIb) , (VIc) , (VId) wherein W₂ is COOH is carried out according to the method described in 3.3.c); 4.6.d) The reaction of the compound of formula (He) wherein R_4f is (B₆) , (C₆) , (D₃) or (E₃) with a compound of formula (Via) , (VIb) , (VIc) , (VId) wherein W₂ is COCl may be carried out according to the method described in 2.1.b); 4.6.e) the reaction of the compound of formula (He) wherein R_4f is (B₆) , (C₆) , (D₃) or (E₃) with a compound of formula (Via), (VIb), (VIc), (VId) wherein W₂ is -C(O)OR_B is carried out according to the method described in 2.1. a), and

4.7) when Q is Qi, by reacting the compound obtained in steps 4.6. a) -4.6. e) according to the method described in 1.3) and

4.8) deprotecting the compounds obtained in step 4.6) or 4.7) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4^nd edition. 5) Preparation of compound (lie)

The compounds of formula (Hc) wherein R₂, R₃, R₄, R_4a, R₅, R₆, R_6a, R₇, R_7a, Rs, Rβa/ R9, Rio, Rioa are as above defined and W is -COCl are prepared starting from the compounds obtained in 1.3), according to methods known in the literature.

6) Preparation of compound (Ilia) The compounds of formula (Ilia) wherein R_A, R₂, R3 are as above defined and Q is Qi are commercially available or can be obtained according to methods known in the literature. The compounds of formula (Ilia) wherein R_A, R₂, R3 are as above defined and Q is ONO2 can be obtained by reacting the compound (Ilia) wherein Q is Qi with a nitrate source as above described. 7) Preparation of the following compounds

(Ai: Wi-R^la'-CH(NHR^2a) -C (0) -Q-Y' (Bi) Wi-R^la'-CH (COOP)NH-C (0) -Y'

(Ci) Wi-R^la'-CH(COOP) -0-C (0) -Y'

(A₄) W₃-R¹-CH(NHR^2a) -C (0) -0-Y' (B₄) W₃-R^CH(COOP)NH-C(O)-Y' (C₄) W₃-R^CH(COOP)-O-C(O)-Y' (Di) W₃-C (O)CH(R³) -NH-C (0) -Y'

(Ei) W₃-C (0) CH₂-CH (R⁴) -NH-C (0) -Y'

wherein

Wi is H, W₃ is -OH,

Rla' R 2a R³, R⁴, P and Y' are as above defined and

R¹ is selected from the group R^lb) as above defined, can be synthesized

7.1) by reacting a compound of formula (A₇) P₄-R^la'-CH(NHR^2a) -C (0) -OH (A₈) PO-R^CH (NHR^2a) -C (0) -OH

P, Pi, R^±d , R^2a are as above defined, R¹ is selected from the group R^lb) as above defined,

P₄ is a hydroxyl protecting group, with a compound of formula

(Via) W₂-Ri₃-CH(Q)R₁₄

(VIb) W₂-Ri₃-CH (Q) - (CRi₅Ri₆) t^~CH (Q) R₁₄ (VIc) W₂- [ (CH₂)₀-X]p-[ (CH₂) r-X] s- (CH₂) _q- (CRi₅Ri₆) t^~CH (Q) R_i4

(VId) W₂- [ (CH₂)₀-X]_p-[ (CH₂) _r-X]_s- (CH₂) _q-CH (Q) -(CRi₅Ri₆) t-

CH(Q)Ri₄ wherein

Q, X, o, p, r, s, t, Ri₃, Ri₄, Ri₅, Ri₆ are as above defined, W₂ is HO-, Cl, Br, I,

7.1. a) the reaction of a compound of formula (A₇), (A₈)

(G₄), (H₄), (I₄) with a compound of formula (Via) (VIb),

(VIc) , (VId) wherein W₂ is Cl, Br, I is carried out according to the method described in 3.3. a) 7.1.b) The reaction of a compound of formula (A₇), (A₈)

(G₄), (H₄), (I₄) with a compound of formula (Via) (VIb),

(VIc) , (VId) wherein W₂ is OH is carried out according to the method described in 2.1.c) .

7.2) or by reaction a compound of formula (B₇) P₄-R^la'-CH(COOP) -NH₂

(C₇) P₄-R^la' -CH (COOH) -OH

(D₄) POC (0) -CH(R³) -NH₂

(E₄) POC(O) -CH₂-CH(R⁴) -NH₂

(B₈) PO-R^CH (COOP) -NH₂ (C₈) PO-R^CH (COOH) -OH wherein

P, R^la' , R³, R⁴ and Pare as above defined and

P₄ is a hydroxyl protecting group, R¹ is selected from the group R^lb) as above defined, with a compound of formula

(Via) W₂-Ri₃-CH(Q)R₁₄

(VIb) W₂-Ri₃-CH (Q) - (CRi₅Ri₆) t~CH (Q) R₁₄

(VIc) W₂- [ (CH₂)O-X_-P-. (CH₂) _r-X]_s- (CH₂) _q- (CRi₅Ri₆) t-CH (Q) Ri₄ (VId) W₂- [ (CH₂)₀-X]_p-[ (CH₂) _r-X]_s- (CH₂) _q-CH (Q) -(CRi₅Ri₆) _t-

CH(Q)Ri₄ wherein

Q, X, o, p, r, s, t, Ri₃, Ri₄, Ri₅, Ri₆ are as above defined,

W₂ is -COOH, -COCl or R_BOC (0) - wherein R_B is as above defined;

7.2. a) the reaction of a compound of formula (B₇), (B₈),

(C₇) , (C₈) , (D₄) , (E₄) with a compound of formula (Via) ,

(VIb) , (VIc) , (VId) wherein W₂ is COOH is carried out according to the method described in 3.3.c), 7.2.b) the reaction of a compound of formula B₇), (B₈),

(C₇) , (C₈) , (D₄) , (E₄) with a compound of formula (Via) ,

(VIb) , (VIc) , (VId) wherein W₂ is -COCl is carried out according to the method described in 2.1.b) .

7.2.c) the reaction of a compound of formula B₇), (B₈), (C₇) , (C₈) , (D₄) , (E₄) ) with a compound of formula (Via) ,

(VIb), (VIc), (VId) wherein W₂ is R_BOC (0) - is carried out according to the method described in 2.1. a), and

7.3) when Q is Qi, by reacting the compound obtained in the steps 7.1. a), 7.1.b), 7.2. a) -7.2. c) with a nitrate source according to the method described in 1.3) and 7.4) deprotecting the compounds obtained in steps 6.1) and 6.2) or 6.3) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4^nd edition. Fluoride ion is the preferred method for removing the silyl ether group.

The compounds of formula (A₇), (A₈), (B₇), (B₈), (C₇), (C₈), (D₄), (E₄), (G₄), (H₄), (I₄) are commercially available or can be obtained according to methods known in the literature 8) The compounds of formula (A₄) W₃-R¹-CH(NHR^2a) -C (O) -O-Y' (B₄) W₃-R¹-CH (COOP)NH-C (O) -Y' (C₄) W₃-R¹-CH(COOP) -O-C (O) -Y' (D₁) W₃-C(O)CH(R³) -NH-C(O) -Y' (E₁) W₃-C (O)CH₂-CH(R⁴) -NH-C (0) -Y' wherein W₃ is R_BO-, R¹ is selected from the group R^lb),R^2a, R³, R⁴ P and Y' are as above defined can be synthesized according to methods known in the literature from the correspondend compounds of formula (A₄) , (B₄) , (C₄) , (D₁) , (E₁) wherein W₃ is -OH.

9) The compounds of formula (Via) , (VIb) , (VIc) , (VId) are commercially available or can be obtained according to methods as known in the literature.

Example 1

Synthesis of (8S, 9S, 1OR, US, 13S, 14S, 17R) -11 -hydroxy- 17- (2- hydroxyacetyl) -10, 13-dimethyl-3-oxo-6, 7,8,9,10,11,12,13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl 4-nitroxybutanoate (Compound (58))

(58)

A) (4' R, 8S, 9S, 1OR, US, 13S, 14S) -2'- (3-bromopropyl) -11- hydroxy-2 ' -methoxy-10, 13-dimethyl-7, 8, 9, 10, 11, 12, 13, 14, 15, 16-decahydrospiro [cyclopenta [a] phenanthrene-17, 4 ' - [ 1, 3] dioxane] -3, 5 ' (6H)-dione

(A) To a solution of prednisolone (1.5 g, 4.16 mmol) in toluene (28 ml) and N, N-dimethylformamide (4 ml), p- toluenesulfonic acid (cat) and trimethyl-4-bromo- orthobutyrate (1.44 ml, 8.3 mmol) were added. The reaction was stirred at room temperature for 17 hours. The mixture was poured in water (55 ml) and extracted with ethyl acetate (55x4 ml) ; the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient n- hexane/ethyl acetate 8/2 (145 ml), to n-hexane/ethyl acetate 3/7 during 1015 ml, n-hexane/ethyl acetate 3/7 (725 ml)) . The product (A) (1.83 g) was obtained.

B) !8S, 9S, 1OR, US, 13S, 14S, 17R) -ll-hydroxy-17- (2-hydroxy acetyl) -10, 13-dimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl 4- bromobutanoate

(B) To a solution of compound (A) (1.73 g, 3.31 mmol) in methanol (59 ml), a 5% aqueous AcOH solution (11.8 ml) was added. The reaction was stirred at reflux for 5 hours. The mixture was concentrated under reduced pressure. The mixture was diluted with dichloromethane (50 ml), washed with saturated aqueous sodium carbonate (2x50 ml) and water (2X50 ml); the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient acetone/dichlorometane 9/1 (145 ml), to acetone/dichlorometane 25/75 during 1015 ml, acetone/dichlorometane 25/75 (435 ml) ) . The product (B) (1.25g) was obtained.

C) (8S, 9S, 1OR, US, 13S, 14S, 17R) -ll-hydroxy-17- (2-hydroxy acetyl) -10, 13-dimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl 4-nitroxy butanoate (Compound (58))

To a solution of compound (B) (1.24 g, 2.44 mmol) in acetonitrile (39 ml), silver nitrate (1.24g, 7.32 mmol) was added. The reaction was heated to 130⁰C for 15 minutes under microwave irradiation. The resulting mixture was cooled, filtered and the solvent was removed under reduced pressure. The residue was diluted with dichloromethane (50 ml) and washed with water (2X50 ml) ; the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient acetone/dichlorometane 9/1 (75 ml) , to acetone/dichlorometane 25/75 during 375 ml, acetone/dichlorometane 25/75 (375 ml)) . The product (0.95 g) was obtained. 1H-NMR: (DMSO), δ: 7.31 (IH, ά, J = 10.1 Hz), 6.17 (IH, d,

J = 10.1 Hz), 5.92 (IH, s), 5.00 (IH, t, J = 6.0 Hz), 4.76

(IH, d, J = 3.0 Hz), 4.50 (2H, t, J = 6.3 Hz), 4.30 (IH, bs), 4.16 (IH, dd, J = 18.3, 6.0 Hz), 4.05 (IH, dd, J =

18.3, 6.0 Hz), 2.74 (IH, t, J = 11.8 Hz), 2.56 (IH, m) , 2.43 (2H, t, J = 7.3 Hz), 2.30 (IH, dd, J = 13.0, 2.5 Hz), 2.06 (2H, m) , 1.89 (3H, m) , 1.68 (3H, m) , 1.54 (IH, m) , 1.38 (3H, s), 1.37 (IH, m) , 1.11 - 0.93 (2H, m) , 0.84 (3H, s) .

Example 2

Synthesis of 4- (nitrooxy) butyl 4- ( (2- ( (8S, 9S, 1OR, US, 13S, 14S, 17R) -ll-hydroxy-17- (4-nitroxy butanoyloxy) -10, 13-dimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl) -2- oxoethoxy) carbonyloxy) -3-methoxybenzoate (Compound (60))

(60)

D) (8S, 9S, 1OR, US, 13S, 14S, 17R) -17- (2- (chlorocarbonyloxy) acetyl) -ll-hydroxy-10, 13-dimethyl-3-oxo-6, 7,8,9,10,11,12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17- yl 4-nitroxybutanoate

(D) To a solution of compound (58) (0.5 g, 1.01 mmol) in tetrahydrofurane (4.8 ml), cooled at 0⁰C and under N₂, a 20% toluene solution of phosgene (3.2 ml, 6.1 mmol) was added. The reaction was stirred at 0⁰C for 1 hour, than at room temperature for 16 hours. The excess of phosgene was removed by heating at 40⁰C for 45 minutes. The solvent was evaporated under vacuum. The crude product (D) (0.61 g) was used in the next step without any purification. E) 4- (nitrooxy) butyl 4- ( (2- ( ( 9R, 1OS, US, 13S, 16S, 17R) -9- fluoro-ll-hydroxy-10 , 13, 16-trimethyl-17- (4- (nitrooxy) butanoyloxy) -3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17- dodecahydro-3H-cyclopenta [a] phenanthren-17-yl) -2- oxoethoxy) carbonyloxy) -3-methoxybenzoate (Compound (60))

To a solution of compound (D) (0.6 g, 1.19 mmol) in dichloromethane (12 ml), diisopropylethylamine (0.21 ml, 1.19 mmol) was added. The reaction was cooled at 0⁰C and vanillic acid 4- (nitrooxy) butyl ester (0,34 g, 1.19 mmol) was added. The reaction was stirred at room temperature for 19 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient n- hexane/ethyl acetate 8/2 (75 ml) , to n-hexane/ethyl acetate 2/8 during 525 ml, n-hexane/ethyl acetate 2/8 (225 ml) ) . The product (0.34 g) was obtained.

¹H-NMR: (DMSO), δ: 7.65 (IH, s), 7.64 (IH, ά, J = 7.9 Hz), 7.39 (IH, d, J = 7.9 Hz), 7.31 (IH, d, J = 10.1 Hz), 6.17 (IH, d, J = 10.1 Hz), 5.93 (IH, s), 5.07 (IH, d, J = 17.2 Hz), 4.91 (IH, d, J = 17.2 Hz), 4.80 (IH, d, J = 3.4 Hz), 4.60 (2H, t, J = 5.5 Hz), 4.51 (2H, t, J = 6.2 Hz), 4.32 (2H, t, J = 5.0 Hz), 3.89 (3H, s), 2.75 (IH, t, J = 12.2 Hz), 2.62 - 2.39 (3H, m) , 2.30 (IH, dd, J = 11.8, 3.7 Hz), 2.15 - 1.49 (15H, m) , 1.38 (3H, s), 1.36 (IH, m) , 1.03 (IH, m) , 0.91 (3H, s) .

Example 3

Synthesis of ( 6S, 9R, 10S, US, 13S, 16R, 17R) -6, 9-difluoro-11- hydroxy-17- (2-hydroxyacetyl) -10, 13, 16-trimethyl-3-oxo- 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H- cyclopenta [a] phenanthren-17-yl 4-nitroxybutanoate (compound (20) )

(20)

F) (4'R, 6S,9R, 10S,llS,13S,16R)-2'- (3-bromopropyl) -6, 9- difluoro-ll-hydroxy-2 ' -methoxy-10, 13, 16-trimethyl- 7,8,9,10,11,12, 13, 14, 15, 16-decahydrospiro [cyclopenta [a] phenanthrene-17, 4 ' - [ 1, 3] dioxane] -3,5' (6H)-dione

(F) To a solution of flumethasone (0.9 g, 2.19 mmol) in toluene (15 ml) and N, N-dimethylformamide (2.1 ml), p- toluenesulfonic acid (cat) and trimethyl-4-bromo- orthobutyrate (0.76 ml, 4.38 mmol) were added. The reaction was stirred at room temperature for 72 hours. The mixture was poured in water (40 ml) and extracted with ethyl acetate (40x4 ml) , the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient n- hexane/ethyl acetate 8/2 (145 ml), to n-hexane/ethyl acetate 3/7 during 870 ml, n-hexane/ethyl acetate 3/7 (725 ml)) . The product (F) (0.89 g) was obtained. G) (8S,9S,10R, 11S,13S,14S,17R) _₁₁__hydroxy_₁₇_ ₍₂- hydroxyacetyl) -10, 13-dimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl 4- bromobutanoate

(G)

To a solution of compound (F) (0.88 g, 1.53 mmol) in methanol (27 ml), a 5% aqueous AcOH solution (5.5 ml) was added. The reaction was stirred a reflux for 7 hours. The mixture was concentrated under reduced pressure. The mixture was diluted with dichloromethane (30 ml) , washed with saturated aqueous sodium carbonate (2x30 ml) , water

(2X30 ml) , the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient acetone/dichlorometane 9/1 (75 ml) , to acetone/dichlorometane 25/75 during 375 ml, acetone/dichlorometane 25/75 (375 ml) ) . The product (G) (0.74 g) was obtained.

H) (6S, 9R, 1OS, US, 13S, 16R, 17R) -6, 9-difluoro-ll-hydroxy-17- (2-hydroxyacetyl) -10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl 4-nitroxybutanoate (compound (20))

To a solution of compound (G) (0.73 g, 1.31 mmol) in acetonitrile (32 ml), silver nitrate (0.67 g, 3.95 mmol) was added. The reaction was heated to 130⁰C for 15 minutes under microwave irradiation. The resulting mixture was cooled, filtered and the solvent was removed under reduced pressure. The residue was diluted with dichloromethane (40 ml) , washed with water (2X40 ml) , the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography,

(Biotage System, SNAP Cartridge silica 50 g, eluent: gradient acetone/dichlorometane 9/1 (75 ml) , to acetone/dichlorometane 25/75 during 375 ml, acetone/dichlorometane 25/75 (375 ml)) . The product (0.57 g) was obtained.

¹H-NMR: (DMSO), δ: 7.25 (IH, d, J = 10.1 Hz), 6.29 (IH, d, J = 10.1 Hz), 6.11 (IH, s), 5.63 (IH, dq, J_H-_F = 48.8, J_H-_H = 10.8, 6.5 Hz), 5.48 (IH, d, J = 3.6 Hz), 5.07 (IH, t, J = 5.9 Hz), 4.51 (2H, t, J = 6.4 Hz), 4.17 (IH, dd, J = 17.2, 5.9 Hz), 4.16 (IH, bs), 4.05 (dd, J = 17.2, 5.9, IH), 3.28 - 3.16 (IH, m) , 2.64 - 2.38 (3H, m) , 2.25 (IH, m) , 2.17 - 2.01 (2H, m) , 1.99 - 1.72 (3H, m) , 1.66 (IH, d, J = 13.8 Hz), 1.49 (IH, m) , 1.48 (3H, s), 1.23 (IH, m) , 0.93 (3H, s) , 0.84 (3H, d, J = 6.9 Hz) .

Example 4

Synthesis of 4- (nitrooxy) butyl 4- ( (2- ( (6S, 9R, 10S, US, 13S, 16R, 17R) -6, 9-difluoro-ll-hydroxy-17- (4- nitroxybutanoyloxy) -10, 13, 16-trimethyl-3-oxo-6, 7,8,9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl) -2-oxoethoxy) carbonyloxy) -3- methoxybenzoate (Compound (22))

(22)

I) (6S, 9R, 1OS, US, 13S, 16R, 17R) -17- (2- (chlorocarbonyloxy) acetyl) -6, 9-difluoro-ll-hydroxy-10, 13, 16-trimethyl-3-oxo- 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H- cyclopenta [a] phenanthren-17-yl 4-nitroxybutanoate

(D

To a solution of compound (20) (0.35 g, 0.64 mmol) in tetrahydrofurane (3.1 ml), cooled at 0⁰C and under N₂, a

20% toluene solution of phosgene (2.03 ml, 3.87 mmol) was added. The reaction was stirred at 0⁰C for 1 hour and at room temperature for 22 hours. The excess of phosgene was removed by heating at 40⁰C for 45 minutes. The solvent was evaporated under vacuum. The crude product (I) (0.38 g) was used in the next step without any purification. L) 4- (nitrooxy) butyl 4- ( (2- ( ( 6S, 9R, 1OS, US, 13S, 16R, 17R) - 6, 9-difluoro-ll-hydroxy-17- (4-nitroxybutanoyloxy) -10, 13, 16- trimethyl-3-oxo-6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17- dodecahydro-3H-cyclopenta [a] phenanthren-17-yl) -2- oxoethoxy) carbonyloxy) -3-methoxybenzoate Compound (22)

To a solution of compound (I) (0.38 g, 0.63 mmol) in dichloromethane (7 ml), diisopropylethylamine (0.12 ml, 0.69 mmol) was added. The reaction was cooled at 0⁰C and vanillic acid 4- (nitrooxy) butyl ester (0,19 g, 0.69 mmol) was added. The reaction was stirred at room temperature for 18 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient n- hexane/ethyl acetate 9/1 (75 ml) , to n-hexane/ethyl acetate 2/8 during 675 ml, n-hexane/ethyl acetate 2/8 (375 ml)) . The product (0.38 g) was obtained.

¹H-NMR: (DMSO), δ 7.65 (IH, s), 7.64 (IH, d, J = 8.1 Hz), 7.39 (IH, d, J = 7.1 Hz), 7.25 (IH, d, J = 10.2 Hz), 6.29 (IH, d, J = 10.2 Hz), 6.11 (IH, s), 5.64 (IH, dq, J_H-_F = 49.0, J_H-_H = 10.6, 6.6 Hz), 5.49 (IH, d, J = 3.1 Hz), 5.16 (IH, d, J = 16.5 Hz), 4.92 (IH, ά, J = 16.5 Hz), 4.60 (2H, t, J = 5.5 Hz), 4.52 (2H, t, J = 6.1 Hz), 4.34 (2H, t, J = 5.1 Hz), 4.19 (IH, m) , 3.89 (3H, s), 2.55 (2H, t, J = 7.4 Hz), 2.51 (IH, m) , 2.25 (IH, m) , 2.19 - 2.02 (2H, m) , 1.98 - 1.74 (8H, m) , 1.66 (IH, d, J = 13.8 Hz), 1.50 (IH, m) , 1.48 (3H, s), 1.23 (IH, m) , 0.99 (3H, s), 0.89 (3H, d, J = 6.7 Hz) .

Claims

A compound of formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

(D wherein :

Ri is -H or Ri is selected from

(A) -R^CH(NHR²) -C (0) -0-Y (B) -R^CH(COOH)NH-C(O)-Y

(C) -R^CH(COOH)-O-C(O)-Y

(D) -C(O)CH(R³) -NH-C(O) -Y

(E) -C (O)CH₂-CH(R⁴) -NH-C (0) -Y

(F) -(Z)-Y (G)

(H)

:D wherein :

R is selected from R^la)

-C(O)-S-CH₂-, -C(O)O-CH(CH₃)-, -C(O)O-CH₂-;

R^lb) -C(O)-CH₂-, -C(O)- (CH₂) ₂-;

R² is -H or -C(O)CH₃;

R³ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl;

R⁴ is -H, -CH₃, isopropyl, isobutyl, sec-butyl, methylthio- (CH₂) ₂-, benzyl;

Z is -C(O) or -C(O)-X", wherein X" is 0, S or NR₁₁ wherein Rn is H or a C₁-C₄ alkyl;

R₂ is a straight or branched Ci-Cio alkylene;

R₃ is H or a straight or branched Ci-C₄ alkyl;

R₄ is -H, -CH₃;

R_4A is -H, or R₄ and R_4A taken together are =CH₂;

R₅ is -H, Cl;

R_7a is H, or R₇ and R_7A taken together are =0; R₈ is H, Cl, or R₇ and R₈ taken together are the group of formula (V)

Ri₃ is a straight or branched C1-C10 alkylene;

Ri₄ is H or a straight or branched Ci-C₄ alkyl;

R_i5 and R_i6 are H or a straight or branched C1-C10 alkylene; o and r are integers from 1 to 6; p and s are integers from 1 to 6; q is an integer from 0 to 6; t is an integer from 0 to 6;

X is 0, S or NRi₇ wherein Ri₇ is H or a C₁-C₄ alkyl; excluding the following structures of formula (I) :

:IIJ

!H₁₁)

!H₁₁₁)

(H₁,

2. A compound according to claim 1 wherein Ri is -H.

3. A compound according to claim 1 wherein Ri is

(F) -(Z)-Y wherein : Z is -C(O) or -C(O)-X", wherein X" is 0, S or NRn wherein Rn is H or a C₁-C₄ alkyl; Y is selected from -Ri₃-CH(ONO₂)Ri₄

-Ri₃-CH (ONO₂) - (CRi₅Ri₆) t^~CH (ONO₂) R_i4 -[ (CH₂) o-X]p-[ (CH₂) r-X] s- (CH₂) _q- (CRi₅Ri₆) t-CH (ONO₂)Ri₄

Ri₃ is a straight or branched Ci-Cio alkylene, Ri₄ is H or -CH₃, R₁₅ and R_i6 at each occurrence are independently H or -CH₃, o and r are integers from 1 to 4, p and s are integers from 1 to 4, q is an integer from 0 to 4, t is 0 or 1 x is o.

4. A compound according to claim 1 wherein Ri is (G)

(H)

:D wherein : Y is selected from -Ri₃-CH(ONO₂)Ri₄

-Ri₃-CH (ONO₂) - (CRi₅Ri₆) t^~CH (ONO₂) R_i4

- [ (CH₂) o-X] p- [ (CH₂) _r-X] _s- (CH₂) _q- (CRi₅Ri₆) t^~CH (ONO₂) R_i4 wherein Ri₃ is a straight or branched Ci-Cio alkylene, Ri₄ is H or -CH₃,

Ri₅ and R_i6 at each occurrence are independently H or -CH₃, o and r are integers from 1 to 4, p and s are integers from 1 to 4, q is an integer from 0 to 4, t is 0 or 1, X is 0.

5. A compound according to claim 1 wherein

Ri is

(A) -R^CH(NHR²) -C (0) -0-Y (B) -R^CH(COOH)NH-C(O)-Y

(C) -R^CH (COOH) -0-C(O)-Y

(D) -C (O)CH(R³) -NH-C (0) -Y

(E) -C(O)CH₂-CH(R⁴) -NH-C(O) -Y wherein : Y is selected from -Ri₃-CH(ONO₂)Ri₄

-Ri₃-CH (ONO₂) - (CRi₅Ri₆) t^~CH (ONO₂) R_i4 wherein

Ri₃ is a straight or branched Ci-Cio alkylene, Ri₄ is H or -CH₃,

Ri₅ and Ri₆ at each occurrence are independently H or -CH₃, t is 0 or 1.

6. A compound according to claim 5 wherein R¹ of R^la) is

R¹ of R^lb) is -C(O)-CH₂-, R³ is H or -CH₃, R⁴ is -H or -CH₃.

7. A compound according to claim 1 selected from the followings 

8. A compound according to claim 1 for use as medicament.

9. A compound according to any one of claims 1-7 for use in the treatment of inflammatory diseases.

10. A compound according to any one of claims 1-7 for use in the treatment of rheumatic diseases, renal and bronchial pathologies, ocular and dermatological diseases, autoimmune diseases, tumoral processes, also in combination with chemotherapeutic and/or radiotherapeutic treatments, in neurodegenerative diseases, for example in spinal lesions from trauma and in the post-transplant therapy.

11. Use of a compound according to any one of claims 1-7 for the preparation of medicaments for the treatment of inflammatory diseases.

12. Use of a compound according to any one of claims 1-7 for the preparation of medicaments for the treatment of rheumatic diseases, renal and bronchial pathologies, ocular and dermatological diseases, autoimmune diseases, tumoral processes, also in combination with chemotherapeutic and/or radiotherapeutic treatments, in neurodegenerative diseases, for example in spinal lesions from trauma and in the post-transplant therapy.

13. A pharmaceutical composition comprising a pharmaceutically effective amount of at least a compound according to claim 1, and a pharmaceutical acceptable carrier.